Whole brain irradiation (WBI) is an effective treatment for brain tumors and metastases but 50% or more of the long-term survivors treated with WBI suffer cognitive deficits attributed to radiation-induced injury to normal brain tissue. The cellular and molecular mechanisms underlying the deficits are not well understood, but it is clear that radiation kills proliferating cells and also induces acute and chronic oxidative stress and inflammatory responses that alter the function of surviving cells. Although investigations of the mechanisms of radiation-induced brain injury in animal models have begun to reveal key pathways and mediators, translating the knowledge gained from these studies to the clinic is difficult since experimental studies of radiation-induced brain injury in adult rodents have used, almost without exception, very young adults. In contrast, in the clinical population, the majority of adult patients treated with WBI are 50 years of age or older. Since brain aging is accompanied by changes both in proliferating cell populations and in basal levels of inflammation and oxidative stress, the effects of WBI on the older brain are likely to be substantially different from the effects in young adults. This expectation is supported by our preliminary studies and by epidemiological evidence that aging increases the likelihood and the severity of radiation-induced cognitive decline. Treatment of radiation-induced cognitive dysfunction would benefit tremendously from a better understanding of the cellular and molecular responses that follow WBI, but it is critical to test radiation-induced changes in neurobiological measures and cognitive functions following a clinically relevant regimen of WBI and in animals that best model the relevant clinical population. The experiments proposed here will i) provide the first direct test of the effects of aging on radiation-induced deficits in a range of cognitive functions, ii) clarify the key cellular and molecular events that contribute to those functional changes, and iii) test whether treatment with the peroxisomal proliferator-activated receptor (PPAR)? agonist, pioglitazone, an anti-inflammatory agent, prevents radiation-induced cognitive dysfunction in old rats. The information that will be provided by this quantitative analysis of radiation-induced injury in young and old rats is critical to translational efforts to develop therapies to prevent or ameliorate radiation-induced cognitive dysfunction. In the absence of such studies, one runs the significant risk of targeting mechanisms of injury that may be of lesser significance in the primary clinical population. PUBLIC HEALTH RELEVANCE: This research is relative to public health because it will test the effects of a clinically relevant radiation treatment on the development of brain injury and cognitive deficits in an animal model that is amenable to experimental manipulation and that appropriately reflects the primary clinical population, middle age and older adults. Such studies will facilitate the development of new and more efficacious treatments to prevent or reduce radiation-induced brain injury and thereby provide benefits to cancer patients.